2-imino-6-polyfluoroalkoxybenzothiazole derivatives, and pharmaceutical compositions containing them

ABSTRACT

Compounds of formula: ##STR1## and their salts, in which R 1  represents polyfluoroalkoxy, and R 2  represents alkyl, alkenyl (3-6 C), [cycloalkyl (3-6 C)]-alkyl, carbamoylalkyl, dialkylcarbamoylalkyl, acylaminoalkyl, phenylthioalkyl, hydroxyalkyl, cyanoalkyl, sulphamoylethyl, N-alkylsulphamoylethyl, pyridylthioalkyl, pyridiylalkylthioalkyl, pyridylsulphinylalkyl, alkynyl (3-6 C), phenylsulphinylalkyl, halophenylthioalkyl, (2,2,2-trifluoroethylthio)alkyl, 2-dialkylaminopropyl, pyrimidinylsulphinylalkyl, pyridylalkylsulphinylalkyl, halophenylsulphinylalkyl or (2,2,2-trifluoroethylsulphinyl)alkyl are useful in the treatment of medical conditions associated with the effects of glutamate.

This is a Continuation X Division of U.S. application Ser. No. 449,810,filed Dec. 13, 1989, now U.S. Pat. No. 4,980,356.

The present invention provides 2-imino-6-polyfluoroalkoxybenzothiazolederivatives of formula: ##STR2## and their salts, in Which

R₁ represents polyfluoroalkoxy, and

R₂ represents alkyl, alkenyl (3-6 C), [cycloalkyl(3-6C)]alkyl,carbamoylalkyl, dialkylcarbamoylalkyl, acylaminoalkyl, phenylthioalkyl,hydroxyalkyl, cyanoalkyl, sulphamoylethyl, N-alkylsulphamoylethyl,pyridylthioalkyl, pyridylalkylthioalkyl, pyridylsulphinylalkyl, alkynyl(3-6 C), phenylsulphinylalkyl, halophenylthioalkyl,(2,2,2trifluoroethylthio)alkyl, 2-dialkylaminopropyl,pyrimidinylsulphinylalkyl, pyridylalkylsulphinylalkyl,halophenylsulphinylalkyl or (2,2,2-trifluoroethylsulphinyl)alkyl.

Except where otherwise stated, in the definitions above and thosementioned below, the alkyl radicals and alkyl and alkoxy portionscontain 1 to 4 carbon atoms each in a straight or branched chain. Theaddition salts of the compounds of formula (I) with inorganic or organicacids are part of the invention.

Preferred polyfluoroalkoxy radicals are trifluoromethoxy,pentafluoroethoxy, 2,2,2-trifluoroethoxy, I,1,2,2tetrafluoroethoxy and2,2,3,3,3-pentafluoropropoxy.

The compounds of formula (I) in which R2 represents cyanoalkyl,carbamoylalkyl, sulphamoylethyl or N-alkyl-sulphamoyl-ethyl, may beobtained by the action of bromine and an alkali metal thiocyanate on acompound of formula: ##STR3## in which R₁ has the same meanings as inthe formula (I) and R₂ has the same meaning as that given above.

This reaction is generally performed in acetic acid, at a temperature ofapproximately 20.C. Potassium thiocyanate is preferably used as thealkali metal thiocyanate.

The derivatives of formula (II) in which R₂ represents cyanoalkyl may beobtained by the action of a 4-polyfluoro-alkoxyaniline on a derivativeof formula:

    Hal-R.sub.2                                                (III)

in which Hal represents halogen and R₂ represents cyanoalkyl.

This reaction is generally performed in an inert organic solvent orwater, at a temperature between 50.C and the boiling point of thesolvent.

4-Polyfluoroalkoxyanilines may be obtained by application or adaptationof the methods described by W.A. SHEPPARD, J. Org. Chem., 29,1 (1964);in Beilstein 12,1166 and in U.S. Pat. Nos. 3,920,444, US 2,436,100, DE3,195,926, DE 2,606,982 and EP 205,821.

The derivatives of formula (II) for which R2 denotes a carbamoylalkylmay be obtained from the corresponding nitriles by any method known tothose skilled in the art enabling a nitrile to be converted into anamide.

It is preferable to employ sulphuric acid, at a temperature of between60 C and 100 C.

The derivatives of formula (II) for which R2 represents sulphamoylethylor N-alkylsulphamoylethyl may be obtained by the action of a compound offormula: ##STR4## in which R₁ has the same meanings as in the formula(I), with ammonium hydroxide or an alkylamine.

This reaction is generally performed in an inert solvent such as aketone (acetone, methyl ethyl ketone, etc.) or an aromatic solvent(benzene, toluene, etc.), at a temperature between 30.C and the boilingpoint of the solvent.

The derivatives of formula (IV) may be obtained by the action of a4-polyfluoroalkoxyaniline on vinylsulphonyl fluoride. This reaction ispreferably performed in an inert solvent such as dimethylformamide, at atemperature in the region of 20° C.

Vinylsulphonyl fluoride may be obtained according to the methoddescribed by J.J. KRUTAK et al., J. Org. Chem., 44(22), 3847( 1979).

The derivatives of formula (I) in which R₂ represents pyridylthioalkylor pyridylalkylthioalkyl may be prepared by the action of a compound offormula: ##STR5## in which R₁ has the same meanings as in the formula(I), R₃ represents alkylene (1-4 C) and R4 represents a reactive groupsuch as a methanesulphonyl or p-toluenesulphonyl radical, on amercaptopyridine or a pyridylalkyl mercaptan, followed by hydrolysis ofthe product obtained.

This reaction is generally performed in an inert solvent such asdimethylformamide, at a temperature in the region of 20 C. Thehydrolysis is accomplished by means of a base such as concentratedammonia solution, at the boiling point of the reaction medium.

The derivatives of formula (V) may be prepared by the action of acompound of formula: ##STR6## in which R₁ and R₃ have the same mean (V),on methanesulphonyl chloride or p-toluenesulphonyl chloride.

This reaction is preferably performed either in an inert solvent such asbenzene, toluene, chloroform or methylene chloride, in the presence of atertiary amine such as triethylamine, at a temperature in the region of20° C., or in pyridine at a temperature in the region of 0° C.

The derivatives of formula (VI) may be obtained by the action of acompound of formula: ##STR7## in which R₁ and R₃ have the same meaningsas in the formula (V), on ethyl trifluoroacetate.

This reaction is generally performed in an alcohol, in the presence of atertiary base such as triethylamine, at a temperature in the region of20° C.

The derivatives of formula (VII) may be obtained by the action of a2-amino-6-polyfluoroalkoxybenzothiazole on an alcohol of formula:

    Hal R.sub.3 OH                                             (VIII)

in which Hal denotes a halogen atom and R₃ has the same meanings as inthe formula (VII).

This reaction is performed in an alcohol, at the boiling point of thesolvent.

2-Amino-6-polyfluoroalkoxybenzothiazoles may be prepared by applicationor adaptation of the method described by L.M. YAGUPOL'SKII et al., Zh.Obsch. Khim., 33(7), 2301 (1963).

The compounds of formula (I) in which R2 represents alkyl, alkenyl,cycloalkylalkyl, dialkylcarbamoylalkyl, acylaminoalkyl, phenylthioalkyl,hydroxyalkyl, alkynyl, halophenylthioalkyl,(2,2,2-trifluoroethylthio)alkyl or 2dialkylaminopropyl may be preparedby the action of an amino derivative of formula: ##STR8## on a compoundof formula:

    R.sub.2 -X                                                 (X)

in which formulae R₂ has the same meanings as above, R₁ has the samemeanings as in the formula (I) and X denotes a reactive group such astosyloxy radical or a halogen (preferably chlorine, bromine or iodine)atom.

This reaction is preferably performed in an inert solvent such as analcohol, (e.g. ethanol or propanol), a ketone (e.g. acetone or methylethyl ketone) or dimethylformamide, at a temperature between 10° C andthe boiling point of the solvent, optionally in the presence of sodiumiodide and optionally after melting the compounds of formulae (IX) and(X) at 130°-140° C.

The derivatives of formula (X) for which R₂ denotes an alkynyl radicalmay be obtained by application or adaptation of the methods described inBeilstein, 1, IV, 970 and 974.

The derivatives of formula (X) for which R₂ denotes ahalophenylthioalkyl radical may be obtained by application or adaptationof the method described by H.P.S. CHAWLA et al., J. Med. Chem., 13(3),480 (1970).

The derivatives of formula (X) in which R₂ represents(2,2,2-trifluoroethylthio)alkyl may be obtained by the action of acompound of formula:

    HO-R.sub.2                                                 (XI)

in which R₂ has the same meanings as above, on carbon tetrachloride, inthe presence of triphenylphosphine.

This reaction is generally performed at the boiling point of thereaction medium.

The derivatives of formula (XI) in which R₂ represents(2,2,2-trifluoroethylthio)alkyl may be obtained by application oradaptation of the method described by R.C. TERRELL et al., J. Org.Chem., 30(12), 4011 (1965).

The other compounds of formula (X) which are not commercially availablemay be prepared by application or adaptation of the method described byW.C. HOWELL, J. Amer. Chem. Soc., 78, 3843 (1956) and the methodsdescribed in the examples.

The compounds of formula (I) in which R₂ representspyridylalkylsulphinylalkyl, phenylsulphinylalkyl, pyridylsulphinylalkyl,pyrimidinylsulphinylalkyl, halophenylsulphinylalkyl or(2,2,2-trifluoroethylsulphinyl)alkyl may be prepared by oxidation of thecorresponding derivatives for which R2 denotes a pyridylalkylthioalkyl,phenylthioalkyl, pyridylthioalkyl, pyrimidinylthioalkyl,halophenylthioalkyl or (2,2,2-trifluoroethylthio)alkyl.

This oxidation may be accomplished by means of m-chloroperbenzoic acid,in an alcohol, at a temperature in the region of 20° C.

The derivatives in which R₂ represents phenylthioalkyl may be preparedby the action of a 2-amino-6-polyfluoro-alkoxybenzothiazole on ahaloalkylthioalkyl compound.

This reaction is generally performed in an organic solvent such asethanol, propanol, methyl ethyl ketone or dimethylformamide, at atemperature between 60° C. and the boiling point of the solvent.

The derivatives in which R₂ represents pyrimidinylthioalkyl may beprepared by the action of a mercaptopyrimidine on a compound of formula(V).

The reaction mixtures obtained by the various processes described aboveare treated according to conventional physical methods (evaporation,extraction, distillation, crystallization, chromatography, etc.) orchemical methods (salt formation, etc.).

The compounds of formula (I), in free base form, can be optionallyconverted into addition salts with an inorganic or organic acid, by theaction of such an acid in an organic solvent such as an alcohol, ketone,ether or chlorinated solvent.

The compounds of formula (I) and their salts possess advantageouspharmacological properties. These compounds are useful in the treatmentof medical conditions associated with the effects of glutamate in whichit is desirable to inhibit such effort at least partially. They areactive with respect to glutamate-induced convulsions, and are henceuseful in the treatment and prevention of convulsive phenomena,schizophrenic disorders, and in particular the deficiency forms cfschizophrenia, sleep disorders, phenomena linked to cerebral ischaemiaand also neurological conditions in which glutamate may be implicated,such as Alzheimer's disease, Huntington's chorea, amyotrophic lateralsclerosis and olivopontocerebellar atrophy.

The activity of the compounds of formula (I) with respect toglutamate-induced convulsions was determined according to a techniquebased on that of I.P. LAPIN, J. Neural. Transmission, vol. 54, 229-238(1982); intracerebroventricular injection of glutamate being performedaccording to a technique based on that of R. CHERMAT and P. SIMON, J.Pharmacol. (Paris), vol. 6, 489-492) (1975). Their ED50 does not exceed10 mg/kg.

The compounds of formula (I) possess low toxicity. Their LD₅₀ is above15 mg/kg when administered i.p. in mice.

For medicinal use, the compounds of formula (I) may be employed as theyare, or in the form of pharmaceutically acceptable salts, i.e. saltswhich are non-toxic at the doses at which they are used.

As examples of pharmaceutically acceptable salts, the addition saltswith inorganic or organic acids, such as acetate, propionate, succinate,benzoate, fumarate, maleate, oxalate, methanesulphonate, isethionate,theophyllineacetate, salicylate, sulphate, nitrate and phosphate, may bementioned.

The examples which follow illustrate the invention.

EXAMPLE 1

Bromine (3.2 g; 1 cc) is added at room temperature to3-(4-trifluoromethoxyanilino)propionitrile (3 g) and potassiumthiocyanate (7.8 g) dissolved in acetic acid (50 cc). Stirring ismaintained for 12 hours at this temperature. The mixture is evaporatedto dryness at 80° C. under reduced pressure (20 mm Hg; 2.7 kPa). Theresidue obtained is taken up with water (100 cc) and the pH is broughtto 9-10 by adding concentrated sodium hydroxide (10N). After extractionwith ethyl acetate (2×50 cc, washing of the combined phases with water(2×20 cc), drying over anhydrous magnesium sulphate and evaporation todryness at 40° C. under reduced pressure (20 mm Hg; 2.7 kPa), a brownoil is isolated. This oil is dissolved in acetone (100 cc) and oxalicacid (2 g) is added.2-Imino-3-(2-cyanoethyl)-6-trifluoromethoxy-benzothiazoline (5.5 g) isthereby isolated in the form of a monooxylate, m.p. 180° C.

3-(4-Trifluoromethoxyanilino)propionitrile may be prepared in thefollowing manner: 4-trifluoromethoxyaniline (17.7 g) and3-bromopropionitrile (6.7 g) in water (20 cc) are brought to reflux withstirring for 12 hours. The solution is the cooled and taken to drynessat 80.C under reduced pressure (20 mm Hg; 2.7 kPa). The residue obtainedis purified by flash chromatography on a silica column under a stream ofnitrogen at moderate pressure (0.5-1.5 bars), with a mixture ofcyclohexane and ethyl acetate (80:20 by volume) as eluent. A yellow oil(8.7 g) is obtained.

EXAMPLE 2

The procedure is as in Example 1, starting with 3-(4-trifluoromethoxyanilino)propionamide (4.2 g), potassium thiocyanate (6.6g) and bromine (2.7 g; 0.85 cc) in acetic acid (50 cc). The mixture isstirred at a temperature of approximately 20.C for 12 hours. Water (100cc) is added and the pH is brought to 9-10 with concentrated sodiumhydroxide (10N). After extraction with ethyl acetate (2×50 cc), dryingof the combined organic phases over anhydrous magnesium sulphate andevaporation to dryness at 40.C under reduced pressure (20 mm Hg; 2.7kPa), is isolated, which solid is recrystallized in boiling acetonitrile(100 cc). 3(2-Imino-6-trifluoromethoxy-3-benzothiazolinyl)propionamide(2.3 g), m.p. 219.C, is isolated.

3-(4-Trifluoromethoxyanilino)propionamide may be prepared in thefollowing manner: 3-(4-trifluoromethoxyanilino)propionitrile (5.4 9),obtained in Example 1, and concentrated sulphuric acid (20 cc) areheated to 90° C. for 2 hours. After cooling to a temperature of 20° C.,this solution is added to ice (250 g) and the pH is brought to 9-10 withconcentrated sodium hydroxide (10N).3-(4Trifluoromethoxyanilino)propionamide (4.2 g), m.p. 76.C, is therebyisolated directly.

EXAMPLE 3

Bromine (2.3 g), dissolved in acetic acid (10 cc), is added in thecourse of approximately 15 minutes to a mixture of2-(p-trifluoromethoxyanilino)ethanesulphon-amide (4.1 g) and potassiumthiocyanate (5.6 g) in the same solvent (20 cc). The reaction iscontinued for 15 hours at a temperature in the region of 20 C. After theaddition of distilled water (50 cc), the reaction medium is neutralizedwith 30% strength sodium hydroxide. The precipitate formed is filteredoff and then taken up in methanol (50 cc), the mixture is filtered againand the filtrate is concentrated to dryness under reduced pressure (20mm Hg; 2.7 kPa). After formation of the hydrochloride by adding 4.2Nethereal hydrogen chloride (3.6 cc) in a mixture of ethyl ether andmethanol, followed by recrystallization in absolute ethanol (50 cc),2-(2-imino-6-trifluoro-methoxy-3benzothiazolinyl)ethanesulphonamidehydrochloride (2.9 g), subliming at about 225 C, is obtained.

2-(p-Trifluoromethoxyanilino)ethanesulphonamide may be preparedaccording to the following process:2-(ptrifluoromethoxyanilino)ethanesulphonyl fluoride (8.6 g) and 28%strength ammonium hydroxide (30 cc) in acetone (50 cc) are heated toboiling for 1 hour. After cooling of the mixture to a temperature in theregion of 20 C, the acetone is evaporated off under reduced pressure (20mm Hg; 2.7 kPa) and the organic phase extracted with ethyl acetate (3×50cc). After drying over magnesium sulphate, concentration to drynessunder reduced pressure and then chromatography on a silica column with amixture of ethyl acetate and cyclohexane (50:50 by volume) as eluent,2-(p-trifluoromethoxyanilino)ethanesulphonamide (5.5 g) is obtained inthe form of a pinkish oil.

2-(p-Trifluoromethoxyanilino)ethanesulphonyl fluoride may be prepared inthe following manner: vinylsulphonyl fluoride (11.9 g), dissolved indimethylformamide (10 cc), is added dropwise top-trifluoromethoxyaniline (19.1 g) dissolved in dimethylformamide (20cc). The reaction is continued for 2 hours at a temperature in theregion of 20° C. The reaction medium is added to distilled water (300cc) and the aqueous phase extracted with ethyl ether (3×50 cc). Afterdrying and concentration to dryness under reduced pressure (20 mm Hg;2.7 kPa), 2-(p-trifluoromethoxyanilino)ethanesulphonyl fluoride (25.8 g)is obtained in the form of an orange-coloured oil, which is used in thecrude state in the subsequent stages of synthesis.

Vinylsulphonyl fluoride may be obtained according to the methoddescribed by J.J. Krutak et al., J. Org. Chem. 44 (22) 3847 (1979).

EXAMPLE 4

The procedure is as in Example 3, starting withN-methyl-2-(p-trifluoromethoxyanilino)ethanesulphonamide (3.5 g),potassium thiocyanate (4.7 g) and bromine (2.2 g) in acetic acid (30cc). After 18 hours at a temperature in the region of 20 C,neutralization with 30% strength sodium hydroxide and extraction withethyl acetate, a crude product is obtained, which product is convertedto a hydrochloride by adding 4.2N ethereal hydrogen chloride (3 cc) inethanol (25 cc) and recrystallized in absolute ethanol (50 cc). TheN-methyl-2-(2-imino-6-trifluoromethoxy-3-benzothiazolinyl hydrochloridethereby obtained (2.1 g) melts at 242° C.

N-Methyl-2-(p-trifluoromethoxyanilino)ethanesulphonamide may be preparedin the following manner: the procedure is as in Example 3 for thepreparation of 2-(ptrifluoromethoxyanilino)ethanesulphonamide, butstarting with -(p-trifluoromethoxyanilino)ethanesulphonyl fluoride (6.0g) and 40% strength aqueous methylamine (20 cc) in acetone (30 cc).After the mixture is heated for 1 hour to boiling, the acetone isevaporated off and the organic phase extracted with ethyl acetate. Thecrude product obtained is purified by chromatography on a silica columnwith a mixture of ethyl acetate and cyclohexane (50:50 by volume) aseluent. N-methyl-2-(p-trifluoromethoxyanilino)ethanesulphonamide (3.5 g)is obtained in the form of a yellow oil, which is used in the crudestate in the following reactions.

EXAMPLE 5

The procedure is as in Example 3, starting withN-ethyl-2-(p-trifluoromethoxyanilino)ethanesulphonamide (6.1 g),potassium thiocyanate (7.6 g) and bromine (3.6 g) in acetic acid (60cc). After 18 hours at a temperature in the region of 20 C,neutralization with 30% strength sodium hydroxide and extraction withethyl acetate, a crude product is obtained, which product is convertedto a hydrochloride by adding 4.2N ethereal hydrogen chloride (5 cc) inethanol (30 cc) and recrystallized in absolute ethanol (50 cc).N-Ethyl2-(2-imino-6-trifluoromethoxy-3-benzothiazolinyl)ethanesulphonamidehydrochloride (3.0 g), m.p. 240.C, is thereby obtained.

N-Ethyl-2-(p-trifluoromethoxyanilino)ethanesulphonamide may be preparedas in Example 3 for the preparation of2-(p-trifluoromethoxyanilino)ethanesulphonamide, starting with2-(p-trifluoromethoxyanilino)ethanesulphonyl fluoride (6.0 g) and 33%strength aqueous ethylamine (20 cc) in acetone (30 cc). After heatingfor 1 hour to boiling, the acetone is evaporated off and the organicphase extracted with ethyl acetate.N-Ethyl-2-(ptrifluoromethoxyanilino)ethanesulphonamide (6.1 g) isthereby obtained in the form of a brown oil, which is used in the crudestate in the following reactions.

EXAMPLE 6

2-(2-Trifluoroacetylimino-6-trifluoromethoxy-3benzothiazolinyl)ethylpara-toluenesulphonate (8 g) is added to a solution, cooled to atemperature in the vicinity of 20° C., of 4-mercaptopyridine sodium salt(the solution being obtained after cessation of the evolution of gasfrom a solution of 4-mercaptopyridine (1.8 g) in dimethylformamide (30cc) and a suspension of sodium hydride (0.8 g) in 50% strengthdispersion in liquid paraffin, reacted for 1 hour at 50° C.). Thereaction medium is stirred for 2 hours at a temperature in the region of20.C. Ethanol (50 cc), water (10 cc) and concentrated ammonia solution(10N) (20 cc) are then added, in that order, to this solution. Thesolution is brought to reflux for 1 hour and cooled to a temperature inthe region of 20.C. This aqueous solution is extracted withdichloromethane (2×50 cc); the organic phase is dried over anhydrousmagnesium sulphate, filtered and concentrated to dryness at 40.C underreduced pressure (20 mm Hg; 2.7 kPa). The residue obtained is purifiedby flash chromatography on a silica column under a stream of nitrogen atmoderate pressure (0.5-1.5 bars) with ethyl acetate as eluent, and thesolid obtained is treated with oxalic acid (2.4 g) and acetone (10 cc).2-Imino-3-[2-(4-pyridylthio)ethyl]-6-trifluoromethoxybenzothiazoline(3.5 g) is isolated in the form of a dioxalate, m.p. 164° C.

2-(2-Trifluoroacetylimino-6-trifluoromethoxy-3benzothiazolinyl)ethylp-toluenesulphonate may be prepared according to the following process:2-(2-trifluoro-acetylimino-6-trifluoromethoxy-3-benzothiazolinyl)ethanol(19.3 q) is added gradually to p-toluenesulphonyl chloride (19.7 g)dissolved in pyridine (120 cc) cooled to 0° C. The reaction is continuedfor 1 hour at 10°-15° C. The reaction medium is added to distilled water(500 cc) and the organic phase extracted with dichloromethane (3×100cc). After washing with 1N hydrochloric acid (2×50 cc) and then withdistilled water (2×50 cc), drying over magnesium sulphate andconcentration to dryness under reduced pressure (20 mm Hg; 2.7 kPa),2-(2-trifluoroacetylimino-6-trifluoromethoxy-3benzothiazolinyl)ethylp-toluenesulphonate (14.1 g), m.p. 143° C., is obtained.

2-(2-Trifluoroacetylimino-6-trifluoromethoxy-3benzothiazolinyl)ethanolmay be prepared in the following manner:2-(2-imino-6-trifluoromethoxy-3-benzothiazolinyl)ethanol hydrobromide(20.7 g), ethyl trifluoroacetate (9.8 g) and triethylamine (16.1 cc) arestirred in ethanol (100 cc) for 22 hours at a temperature in the regionof 20° C. After concentration to dryness under reduced pressure, theresidue obtained is purified by chromatography on a silica column withethyl acetate as eluent.2-(2-Trifluoroacetylimino-6-trifluoromethoxy-3-benzothiazolinyl)ethanol(19.2 g), m.p. 144° C., is obtained.

2-(2-Imino-6-trifluoromethoxy-3-benzothiazolinyl)ethanol may be preparedaccording to the following process:2-amino-6-trifluoromethoxybenzothiazole (9.4 g) and 2bromoethanol (10 g)in absolute ethanol (30 cc) are heated for 95 hours to boiling. Themixture is then cooled to a temperature in the region of 20.C. Theprecipitate formed is filtered off and washed with ethyl ether (100 cc).2-(2-Imino-6-trifluoromethoxy-3-benzothiazolinyl)ethanol hydrobromide(6.4 g), m.p. 219.C, is obtained.

2-Amino-6-trifluoromethoxybenzothiazole may be prepared according to themethod described by L.M. YAGUPOL'SKII et al., Zh. Obahch. Khim, 33(7),2301 (1963).

EXAMPLE 7

The procedure is as in Example 6, starting with sodium hydride (0.8 g)in 50% strength dispersion in liquid paraffin, 2-pyridylmethyl mercaptan(1.9 g) 2-(2-trifluoro-acetylimino-6-trifluoromethoxy-3-benzothiazoliny(8 g) and dimethylformamide (30 cc). The mixture is stirred for 12 hoursat a temperature in the vicinity of 20° C. Ethanol (50 cc), water (10cc) and concentrated ammonia solution (10N) (20 cc) are added, in thatorder, to this solution. The solution is brought to reflux for 1 hourand cooled to a temperature in the region of 20° C. This aqueou solutionis extracted with dichloromethane (2 x 50 cc), dried over anhydrousmagnesium sulphate, filtered and concentrated to dryness at 40° C. underreduced pressure (20 mm Hg; 2.7 kPa). The residue obtained is purifiedby flash chromatography on a silica column under a stream of nitrogen atmoderate pressure (0.5-1.5 bars), with a mixture of cyclohexane andethyl acetate (50:50 by volume) as eluent.2-Imino-3-[2-(2-pyridylmethylthio)ethyl]-6trifluoromethoxybenzothiazoline(3.5 g), m.p. 125 C, is thereby isolated.

EXAMPLE 8

meta-Chloroperbenzoic acid (90% pure by weight) (1 g) is added in thecourse of ten minutes at a temperature in the region of -10° C., withstirring, to2-imino-3-[2-(2pyridylthio)ethyl]-6-trifluoromethoxy-benzothiazoline(1.9 g) dissolved in chloroform (30 cc). The reaction mixture is stirredfor 1 hour at a temperature in the region of 20° C. and thenconcentrated at 40.C under reduced pressure (20 mm Hg; 2.7 kPa). Theresidue is purified by flash chromatography on a silica column under astream of nitrogen at moderate pressure (0.5-1.5 bars), with a mixtureof ethyl acetate and cyclohexane (70:30 by volume) as eluent. The oilthereby obtained is taken up with diethylether (50 cc) and(RS)-2-imino-3-[2-(2-pyridylsulphinyl)ethyl]-6-trifluoromethoxybenzothiazoline(1 g), m.p. 94.C, is isolated.

2-Imino-3-[2-(2-pyridylthio)ethyl]-6-trifluoromethoxybenzothiazoline maybe prepared in the following manner: the procedure is as in Example 6,starting with sodium hydride (1.6 g) in 50% strength dispersion inliquid paraffin, 2-mercaptopyridine (3.6 g),2-(2-trifluoro-acetylimino-6-trifluoromethoxy-3-benzothiazolinyl)eth (16g) and dimethylformamide (30 cc). The mixture is stirred for 12 hours ata temperature in the vicinity of 20.C. Ethanol (50 cc), water (10 cc)and concentrated ammonia solution (10N) (20 cc) are added, in thatorder, to this solution. The solution is brought to reflux for 1 hourand cooled to a temperature in the region of 20° C. This aqueoussolution is extracted with dichloromethane (2×50 cc), dried overanhydrous magnesium sulphate, filtered and concentrated to dryness at 40C under reduced pressure (20 mm Hg; 2.7 kPa). The residue is taken upwith isopropyl ether (40 cc) and hexane (80 cc).2-Imino-32-(2-pyridylthio)ethyl]-6-trifluoromethoxy-benzothiazoline (8g), m.p. 104.C, is thereby isolated directly.

EXAMPLE 9

m-Chloroperbenzoic acid (0.6 g) is added in the course of approximately10 minutes to2-imino-3-(2-phenylthioethyl)-6trifluoromethoxybenzothiazoline (1.3 g)in absolute ethanol (20 cc) cooled to 0.C. The reaction is continued for3 hours at a temperature in the region of 20 C. The reaction medium isconcentrated to dryness under reduced pressure (20 mm Hg; 2.7 kPa) andthe residue obtained purified by chromatography on a silica column withethyl acetate as eluent.(RS)-2-Imino-3-(2-phenylsulphinylethyl)-6-trifluoromethoxybenzothiazoline(0.7 g) is obtained in the form of a yellowish oil, which is convertedto a hydrochloride, m.p. 10 C.

EXAMPLE 10

1-Bromo-2-butyne (10 g), 2-amino-6-trifluoromethoxybenzothiazole (17 g)and ethanol (30 cc) are heated to reflux for 6 hours. After the mixturehas returned to a temperature in the region of 20.C, the ethanol isevaporated off under reduced pressure (20 mm Hg; 2.7 kPa) and the redsolid obtained is taken up with water (100 cc), alkalinized with 28%strength ammonia solution and extracted with ethyl acetate (300 cc intotal). The organic extract is dried over magnesium sulphate, filteredand evaporated under reduced pressure (20 mm Hg; 2.7 kPa). Theevaporation residue is purified by chromatography on a silica columnwith a mixture of cyclohexane and ethyl acetate (60:40 by volume) aseluent: a cream solid (7.2 g) is obtained, which solid is recrystallizedin a mixture of cyclohexane (100 cc) and ethyl acetate (5 cc) to yield3-(2-butynyl)-2-imino-6-trifluoromethoxybenzothiazoline (5.1 g), m.p.116° C.

1-Bromo-2-butyne may be prepared according to the method described inBEILSTEIN 1, IV 1974.

2-Amino-6-trifluoromethoxybenzothiazole may be obtained according to themethod described by L.M. YAGUPOL'SKII et al., Zh. Obsch. Khim., 33(7),2301 (1963).

EXAMPLE 11

The procedure is as in Example 10, starting with 4-bromo-1-butyne (16 g)and 2-amino-6-trifluoromethoxybenzothiazole (16 g), which are heated toreflux for 5 hours. After purification by chromatography on a silicacolumn with a mixture of cyclohexane and ethyl acetate (50:50 by volume)as eluent, a white solid (1 g) is obtained, which solid is ground inpetroleum ether (40°-65° C.) (6 cc), filtered and dried at 40° C. underreduced pressure (3 mm Hg; 0.4 kPa) to give, finally,3-(3-butynyl)-2-imino-6-trifluoromethoxybenzothiazoline (0.7 g), m.p. 73C.

4-Bromo-1-butyne may be prepared according to the method described inBEILSTEIN 1, IV 970.

EXAMPLE 12

2-Amino-6-trifluoromethoxybenzothiazole (9.4 g) and2-chloro-1-dimethylaminopropane hydrochloride (7.0 g) are heated for 1hour to 130.C. 2-Propanol (20 cc) is added and heating is continued for24 hours to boiling. After cooling of the mixture to a temperature inthe region of 20.C, the precipitate is filtered off and then treatedwith IN sodium hydroxide (80 cc) in distilled water (100 cc). Theresidue obtained by extraction with dichloromethane, drying overmagnesium sulphate and concentration to dryness under reduced pressure(20 mm Hg; 2.7 kPa) is purified by chromatography on a silica columnwith a mixture of ethyl acetate and methanol (80:20 by volume) aseluent.(RS)-3-(2-Dimethylaminopropyl)2-imino-6-trifluoromethoxybenzothiazoline(3.3 g) is obtained in the form of a yellow oil, which is converted to adihydrochloride subliming at about 190° C.

EXAMPLE 13

A mixture of 2-amino-6-trifluoromethoxybenzo-thiazole (9.4 g),1-chloro-2-(4-fluorophenylthio)ethane (15.2 g) and sodium iodide (12 g)in methyl ethyl ketone (30 cc) is heated 48 hours to boiling. Aftercooling of the mixture to a temperature in the region of 20.C, ethylether (50 cc) is added and the precipitate obtained is filtered off. Thelatter is taken up in distilled water (100 cc) and treated with INsodium hydroxide (10 cc). After extraction with dichloromethane (100cc), drying over magnesium sulphate and concentration under reducedpressure (20 mm Hg; 2.7 kPa),2-imino-3-[2-(4-fluorophenylthio)ethyl]-2-imino-6-trifluoromethoxybenzothiazoline(1.4 g) is obtained in the form of a yellow oil, which is converted to ahydrochloride, m.p. 200° C.

1-Chloro-2-(4-fluorophenylthio)ethane may be prepared according to themethod described by H.P.S. CHAWLA et al., J. Med. Chem., 13 (3), 480(1970).

EXAMPLE 14

A mixture of 2-amino-6-trifluoromethoxybenzo-thiazole (5.9 g),1-chloro-2-(2,2,2-trifluoro-ethylthio)ethane (4.8 g) and sodium iodide(3.8 g) in methyl ethyl ketone (20 cc) is heated for 72 hours to boilingand then cooled to a temperature in the region of 20 C. After theaddition of ethyl ether (100 cc), the precipitate formed is filtered offand the filtrate concentrated to dryness under reduced pressure (20 mmHg; 2.7 kPa). The residue obtained is taken up in ethyl acetate (20 cc)and the hydrochloride formed by adding 4.2N ethereal hydrogen chloride(7 cc).2-Imino-3-[2(2,2,2-trifluoroethylthio)ethyl]-6-trifluoromethoxy-benzothiazolinehydrochloride (1.2 g), subliming at about 180° C., is obtained.

1-Chloro-2-(2,2,2-trifluoroethylthio)ethane may be prepared according tothe following process: 2-(2,2,2trifluoroethylthio)ethanol (13.1 g) andtriphenylphosphine (27.8 g) in carbon tetrachloride (60 cc) are heatedfor 3 hours to boiling. After cooling of the mixture to 0° C.,cyclohexane (70 cc) is added, the precipitate formed is filtered off andthe filtrate concentrated to dryness under reduced pressure (20 mm Hg;2.7 kPa). The residue obtained is purified by distillation.1-Chloro-2-(2,2,2-trifluoroethylthio)ethane (4.8 g), b.p. 105.C at 200mm Hg, is obtained.

2-(2,2,2-Trifluoroethylthio)ethanol may be prepared according to thefollowing method: sodium (6.1 g) is added gradually to absolute ethanol(170 cc) at a temperature in the region of 20.C. 2-Mercaptoethanol (18.6cc) is added in the course of approximately 30 minutes to the sodiumethylate thereby formed, followed by the addition of trifluoroethyliodide (25.9 cc). The reaction mixture is brought to boiling for 30minutes and then concentrated to dryness under reduced pressure. Theresidue obtained is taken up with ethyl ether (300 cc), the precipitateformed is filtered off and the filtrate washed with distilled water(3×200 cc). After drying over magnesium sulphate and concentration todryness under reduced pressure, 2-(2,2,2-trifluoroethylthio)ethanol(22.6 g) is obtained in the form of a colourless oil.

EXAMPLE 15

2-Amino-6-trifluoromethoxybenzothiazole (7.1 g) and methyl iodide (4.3g) in absolute ethanol (20 cc) are heated for 18 hours to boiling. Themixture is then cooled to a temperature in the region of 20.C. Theprecipitate formed is separated by filtration and washed with absoluteethanol (2×20 cc). The solid is taken up in distilled water (100 cc)heated to 60° C., and the solution obtained is treated with sodiumhydrogen carbonate (2.6 g). The precipitate is separated by filtrationand recrystallized in a boiling mixture (50 cc) of absolute ethanol anddistilled water (50:50 by volume). 2-Imino-3-methyl-6-trifluoromethoxy

benzothiazoline (2 1 g), m.p. 60°-62° C., is obtained.

2-Amino-6-trifluoromethoxybenzothiazole may be prepared according to themethod described by L.M. YAGUPOL'SKII et al., Zh. Obshch. Khim., 33(7),2301 (1963).

EXAMPLE 16

The procedure is as in Example 15, starting with2-amino-6-trifluoromethoxybenzothiazole (9.4 g) and ethyl iodide (6.2 g)in absolute ethanol (30 cc). The mixture is heated for 51 hours toboiling and then cooled to a temperature in the region of 20° C. Theprecipitate is separated by filtration, treated with 1N sodium hydroxide(20 cc) in distilled water (50 cc) and then extracted with ethyl acetate(200 cc). After concentration to dryness at 40° C. under reducedpressure (20 mm Hg; 2.7 kPa), the residue is taken up in ethyl ether (30cc) and treated with 4.2N ethereal hydrogen chloride (3.1 cc).3-Ethyl-2-imino-6-trifluoromethoxy-benzothiazoline hydrochloride (3.5q), m.p. 234° C., is obtained.

EXAMPLE 17

The procedure is as in Example 15, starting with2-amino-6-trifluoromethoxybenzothiazole (7 g) and 1-iodopropane (10.2 g)in absolute ethanol (20 cc). The mixture is heated for 42 hours toboiling. After cooling to a temperature in the region of 20° C., thereaction mixture is concentrated to dryness at 50.C under reducedpressure (20 mm Hg; 2.7 kPa) and the residue treated with sodiumcarbonate (3.2 g) in distilled water. After extraction with ethylacetate (200 cc) and purification by chromatography on a silica columnwith a mixture of ethyl ether and cyclohexane (65:35 by volume) aseluent, 2-imino-3-propyl-6-trifluoromethoxybenzothiazoline (1.3 g),converted to a hydrochloride subliming at about 180° C., is obtained.

EXAMPLE 18

The procedure is as in Example 15, starting with2-amino-6-trifluoromethoxybenzothiazole (9.4 g) and allyl bromide (9.6g) in absolute ethanol (30 cc). The mixture is heated for 48 hours toboiling. After cooling of the mixture to 0° C., the precipitate isfiltered off, washed with ethyl ether (200 cc) and recrystallized inboiling 2-propanol (70 cc).3-Allyl-2-imino-6-trifluoromethoxybenzothiazoline hydrobromide (4 g),m.p. 225° C., is obtained.

EXAMPLE 19

The procedure is as in Example 15, starting with2-amino-6-trifluoromethoxybenzothiazole (9.4 g) and 4-bromo-1butene(10.8 g) in 2-propanol (30 cc). The mixture is heated for 48 hours toboiling. After cooling of the mixture to a temperature in the region of20.C, the precipitate is filtered off and then washed with 2-propanol(2×50 cc). 3(3-Butenyl)-2-imino-6-trifluoromethoxybenzothiazolinehydrobromide (2.5 g), m.p. 202° C., is obtained.

EXAMPLE 20

The procedure is as in Example 15, starting with2-amino-6-trifluoromethoxybenzothiazole (9.4 g) andbromomethylcyclopropane (12.7 g) in 2-propanol (30 cc). The mixture isheated for 42 hours to boiling. After cooling of the reaction medium toa temperature in the region of 20° C., the precipitate is filtered offand recrystallized in a boiling mixture (30 cc) of ethyl acetate andmethanol (80:20 by volume).3-Cyclopropylmethyl-2-imino-6-trifluoromethoxybenzothiazolinehydrobromide (1.2 g), m.p. 220.C, is obtained.

EXAMPLE 21

2-Amino-6-trifluoromethoxybenzothiazole (9.4 g),N(2-chloroethyl)acetamide (9.7 g) and sodium iodide (13.5 g) in methylethyl ketone (30 cc) are heated for 40 hours to boiling. After coolingto a temperature in the region of 20° C., the reaction medium is addedto distilled water (200 cc), treated with IN sodium hydroxide (40 cc)and then extracted with ethyl acetate (200 cc). After drying overmagnesium sulphate and then concentration to dryness at 40° C. underreduced pressure (20 mm Hg; 2.7 kPa), the residue is purified bychromatography on a silica column with a mixture of ethyl acetate andmethanol (90:10 by volume) as eluent.3-(2-Acetamidoethyl)-2-imino-6-trifluoromethoxybenzothiazoline (2.7 g)is obtained, which product is converted to a hydrochloride subliming atabout 180° C.

EXAMPLE 22

The procedure is as in Example 15, starting with2-amino-6-trifluoromethoxybenzothiazole (9.4 g) and iodoacetamide (14.8g) in methyl ethyl ketone (50 cc). The mixture is heated for 18 hours toboiling and then cooled to a temperature in the region of 20.C. Theprecipitate formed is filtered off, then added to distilled water (100cc) and treated with IN sodium hydroxide (37 cc). The insoluble matteris filtered off, washed with distilled water (100 cc) and recrystallizedin boiling methanol (100 cc).(2-Imino-6-trifluoromethoxy-3-benzothiazolinyl)acetamide (6.2 g), m.p.228° C., is obtained.

EXAMPLE 23

The procedure is as in Example 21, starting with2-amino-6-trifluoromethoxybenzothiazole (9.4 g),N,N-diethylchloroacetamide (12 g) and sodium iodide (13.5 g) in methylethyl ketone (30 cc). The mixture is heated for 16 hours to boiling andthen cooled to a temperature in the region of 20° C. The reaction mediumis added to distilled water (100 cc), treated with 1N sodium hydroxide(50 cc) and then extracted with ethyl acetate (150 cc). After dryingover magnesium sulphate and then concentrating to dryness at 40° C.under reduced pressure (20 mm Hg; 2.7 kPa), the residue is purified bychromatography on a silica column with ethyl acetate as eluent.N,N-Diethyl-(2-imino-6-trifluoromethoxy-3benzothiazolinyl)acetamide (4.2g) is obtained, which product is converted to a hydrochloride, m.p. 223°C.

EXAMPLE 24

The procedure is as in Example 21, starting with2-amino-6-trifluoromethoxybenzothiazole (9.4 g),1-chloro-2phenylthioethane (13.8 g) and sodium iodide (13.5 g) in methylethyl ketone (30 cc). The mixture is heated for 88 hours to boiling andthen cooled to a temperature in the region of 20° C. Ethyl ether (250cc) is added to the reaction medium and the precipitate formed isfiltered off. The solid is suspended in distilled water (250 cc),treated with 1N sodium hydroxide (40 cc) and then extracted with ethylether (100 cc). After drying over magnesium sulphate and filtration,ethyl acetate (150 cc) is added to the filtrate, which is treated with4N ethereal hydrogen chloride (10 cc). The precipitate formed isfiltered off and recrystallized in 2-propanol (85 cc).2-Imino-3-(2-phenylthioethyl)-6- trifluoromethoxybenzothiazolinehydrochloride (5.4 g), m.p. 174° C., is obtained.

EXAMPLE 25

The procedure is as in Example 15, starting with2-amino-6-trifluoromethoxybenzothiazole (9.4 g) and 2-bromoethanol (10g) in absolute ethanol (30 cc). The mixture is heated for 95 hours toboiling and then cooled to a temperature in the region of 20.C. Theprecipitate formed is filtered off and washed with ethyl ether (100 cc).2-(2-Imino-6-trifluoromethoxy-3-benzothiazolinyl)ethanol hydrobromide(6.4 g), m.p. 219.C, is obtained.

EXAMPLE 26

The procedure is as in Example 8, starting with2-imino-3-[2-(2-pyrimidinylthio)ethyl]-6-trifluoromethoxybenzothiazoline(0.5 g) and meta-chloroperbenzoic acid (90% pure by weight) (1 g)dissolved in chloroform (20 cc). The reaction mixture is stirred for 1hour at a temperature in the region of 20.C and then concentrated todryness at 40° C. under reduced pressure (20 mm Hg; 2.7 kPa). Theresidue is purified by flash chromatography on a silica column under astream of nitrogen at moderate pressure (0.5-1.5 bars), with a mixtureof ethyl acetate and methanol (95:5 by volume) as eluent.2-Imino-3-[2-(2-pyrimidinylsulphinyl)ethyl]-6trifluoromethoxybenzothiazoline(0.35 g), m.p. 120.C, is isolated.

2-Imino-3-[2-(2-pyrimidinylthio)ethyl]-6-trifluorocc),methoxybenzothiazoline may be prepared in the following manner: theprocedure is as in Example 6 for the preparation of2-imino-3-[2-(2-pyridylthio)ethyl]-6-trifluoromethoxybenzothiazoline,starting with sodium hydride (0.8 g) in 50% strength dispersion inliquid paraffin, 2-mercaptopyrimidine (1.8 g),2-(2-trifluoro-acetylimino-6-trifluoromethoxy-3benzothiazolinyl)ethylpara-toluenesulphonate (8 g) and dimethylformamide (100 cc). The mixtureis stirred for 12 hours at a temperature in the vicinity of 20.C.Ethanol (100 cc), water (50 cc) and concentrated ammonia solution (10N)(50 cc) are then added, in that order, to this solution. The solution isbrought to reflux for one hour and cooled to a temperature in the regionof 20.C This solution is extracted with dichloromethane (2 100 cc) andthe combined extracts are dried over anhydrous magnesium sulphate,filtered and concentrated to dryness at 40 C under reduced pressure (20mm Hg; 2.7 kPa). The oil thereby obtained is purified by flashchromatography on a silica column under a stream of nitrogen at moderatepressure (0.5-1.5 bars), with a mixture of ethyl acetate and cyclohexane(50:50 by volume) as eluent.2-Imino-[3-2-(2-pyrimidylthio)ethyl]-6-trifluoromethoxybe (2.4 g), m.p.110 C, is isolated.

EXAMPLE 27

The procedure is as in Example 8, starting with2-imino-3-[2-(4-pyridylthio)ethyl]-6-trifluoromethoxybenzothiazoline (2g) and meta-chloroperbenzoic acid (90 pure by weight) (0.68 g) dissolvedin water (25 cc) and dioxane (25 cc). The reaction mixture is stirredfor 12 hours at 25.C and then concentrated to dryness at 40.C underreduced pressure (20 mm Hg; 2.7 KPa) to remove the dioxane. The aqueoussolution is taken to a pH of 12-13 with concentrated ammonia solution(l0N) and then extracted with dichloromethane (2×50 cc). The organicphase is dried over anhydrous magnesium sulphate and concentrated todryness at 40° C. under reduced pressure (20 mm Hg; 2.7 kPa). The oilthereby obtained is purified by flash chromatography on a silica columnunder a stream of nitrogen at moderate pressure (0.5-1.5 bars), with amixture of ethyl acetate and methanol (90:10 by volume) as eluent. Anoil is thereby isolated, which oil, when treated with oxalic acid (0.25g) and acetone (5 cc), gives2-imino-3-[2-(4-pyridylsulphinyl)ethyl]-6trifluoromethoxybenzothiazoline(0.9 g) directly in the form of an oxalate, m.p. 194° C.

The present invention also provides pharmaceutical compositionscomprising at least one compound of formula (I), or a salt of such acompound, in the pure state or in the form of a composition in which itis combined with any other pharmaceutically compatible product, whichcan be inert or physiologically active, and in particular with acompatible pharmaceutically acceptable carrier. The pharmaceuticalcompositions of the invention may be employed orally, parenterally,rectally or topically.

As solid compositions for oral administration, tablets, pills, powders(gelatin capsules, wafer capsules) or granules may be used. In thesecompositions, the active principle according to the invention is mixedwith one or more inert diluents such as starch, cellulose, sucrose,lactose or silica.

These compositions can also comprise substances other than diluents,e.g. one or more lubricants such as magnesium stearate or talc, acolouring, a coating (dragees) or a varnish.

As liquid compositions for oral administration, solutions, suspensions,emulsions, syrups and elixirs of a pharmaceutically acceptable nature,containing inert diluents such as water, ethanol, glycerol, vegetableoils or liquid paraffin, may be used. These compositions can comprisesubstances other than diluents, e.g. wetting products, sweeteners,thickeners, flavourings or stabilizers.

The sterile compositions for parenteral administration can preferably besuspensions, emulsions or non-aqueous solutions. As a solvent orvehicle, water, propylene glycol, a polyethylene glycol, vegetable oils,especially olive oil, injectable organic esters, e.g. ethyl oleate, orother suitable organic solvents may be employed. These compositions canalso contain adjuvants, especially wetting agents, tonicity regulators,emulsifiers, dispersants and stabilizers. The sterilization may becarried out in several ways, e.g. by aseptic filtration, byincorporating sterilizing agents in the composition, by irradiation orby heating. They may also be prepared in the form of sterile solidcompositions which can be dissolved at the time of use in sterile wateror any other sterile injectable medium.

The compositions for rectal administration are suppositories or rectalcapsules which contain, apart from the active products, excipients suchas cocoa butter, semisynthetic glycerides or polyethylene glycols.

The compositions for topical administration can be, e.g., creams,ointments, lotions, eye washes, mouth washes, nasal drops or aerosols.

In human therapy, the compounds according to the invention areespecially useful in the treatment and prevention of convulsivephenomena, schizophrenic disorders, and in particular the deficiencyforms of schizophrenia, sleep disorders, phenomena linked to cerebralischaemia and neurological conditions in which glutamate may beimplicated, such as Alzheimer's disease, Huntington's chorea,amyotrophic lateral sclerosis and olivopontocerebellar atrophy.

The doses depend on the effect sought, the treatment period and theadministration route used; they are generally between 30 and 300 mg perday in oral administration for an adult, with unit doses ranging from 10to 100 mg of active substance.

Generally speaking, the doctor will determine the appropriate dosage inaccordance with the age and weight and all other factors characteristicof the subject to be treated.

The examples which follow illustrate compositions according to theinvention.

EXAMPLE A

Hard gelatin capsules containing 50 mg of active product and having thefollowing composition are prepared according to the usual technique:

    ______________________________________                                        2-imino-3-(2-cyanoethyl)-6-trifluoro-                                                               50 mg                                                   methoxybenzothiazoline                                                        cellulose             18 mg                                                   lactose               55 mg                                                   colloidal silica       1 mg                                                   carboxymethylstarch sodium                                                                          10 mg                                                   talc                  10 mg                                                   magnesium stearate     1 mg                                                   ______________________________________                                    

EXAMPLE B

Tablets containing 50 mg of active product having the followingcomposition are prepared according to the usual technique:

    ______________________________________                                        2-(2-imino-6-trifluoromethoxy-3-benzo-                                                               50 mg                                                  thiazolinyl)ethanesulphonamide                                                lactose                104 mg                                                 cellulose              40 mg                                                  polyvidone             10 mg                                                  carboxymethylstarch sodium                                                                           22 mg                                                  talc                   10 mg                                                  magnesium stearate      2 mg                                                  colloidal silica        2 mg                                                  mixture of hydroxymethylcellulose,                                                                   q.s. 1 finished                                        glycerol and titanium oxide                                                                          film-coated                                            (72:3.5:24.5)          tablet weighing                                                               245 mg                                                 ______________________________________                                    

EXAMPLE C

An injectable solution containing 10 mg of active product and having thefollowing composition is prepared:

    ______________________________________                                        2-imino-3-[2-(2-pyridylsulphinyl)ethyl]-                                                                10     mg                                           6-trifluoromethoxybenzothiazoline                                             benzoic acid              80     mg                                           benzyl alcohol            0.06   cc                                           sodium benzoate           80     mg                                           ethanol, 95%              0.4    cc                                           sodium hydroxide          24     mg                                           propylene glycol          1.6    cc                                           water                     q.s. 4 cc                                           ______________________________________                                    

Although the invention has been described in conjunction with specificembodiments, it is evident that many alternatives and variations will beapparent to those skilled in the art in light of the foregoingdescription. Accordingly, the invention is intended to embrace all ofthe alternatives and variations that fall within the spirit and scope ofthe appended claims. The above references are hereby incorporated byreference.

We claim:
 1. A compound of formula: ##STR9## and its pharmaceuticallyacceptable salts which are nontoxic, in which R₁ representspolyfluoroalkoxy, and R₂ represents pyridylthioalkyl,pyridylalkylthioalkyl, pyridylsulphinylalkyl, orpyridylalkylsulphinylalkyl, the said slkyl and alkoxy portionscontaining 1 to 4 carbon atoms each in a straight or branched chain. 2.A compound according to claim 1, in which R₁ representstrifluoromethoxy, pentafluoroethoxy, 2,2,2-trifluoroethoxy,1,1,2,2-tetrafluoroethoxy or 2,2,3,3,3-pentafluoropropoxy.
 3. Apharmaceutical composition which comprises, as active principle, atleast one compound according to claim 1, or a salt of such a compoundwith an inorganic or organic acid, and a compatible pharmaceuticallyacceptable carrier.
 4. A method for the treatment of a medical conditionassociated with the effects of glutamate which comprises administeringto a subject in need of such treatment an amount of a compound accordingto claim 1, or salt thereof sufficient to inhibit such effects at leastpartially.
 5. A compound as claimed in claim 1 which is2-imino-3-6-trifluoromethoxybenzothiazoline or its addition salts.